Project summary. In our aging society, degenerative complications of chronic disease are on the rise and account for a significant percentage of deaths. Among these, fibrosis is the most common, and yet no therapy capable of mitigating its effects is available. To better understand fibrosis we identified the progenitors that are responsible for it in skeletal muscle and assessed which intracellular signaling pathways are active in these cells specifically in fibrogenic conditions. Like others before us, we identified the Wnt pathway, mediated by ?-catenin, as critical. Next, we generated mice in which ?-catenin can be artificially activated specifically in these fibrogenic progenitors. When this was done the animals not only rapidly developed interstitial fibrosis, but unexpectedly they also suffered from acute muscle atrophy resembling what observed in aging or cancer. This mouse represents a significant advance in that it is the first model in which fibrosis can be induced without damaging the tissue first. In addition, it proves that a fibrotic environment impairs the maintenance of the tissue independently by the disease that led to its development. Here we propose to focus on this last aspect of the problem, and understand how the activation of ?-catenin in fibrogenic progenitors leads to the rapid muscle wasting observed in our mice. This will be done by pursuing two related aims: The first focuses on better understanding changes in the environment of the affected tissue that may lead to muscle atrophy. For example we will be looking at blood flow and vascularization, innervation and at known trophic molecules to see if they are altered. The second will focus on changes caused by ?-catenin activation in the fibrogenic progenitors themselves. We will take advantage of our ability to purify these cells to look at their gene expression profiles, with the goal of identifying changes that could be responsible for our observations. We will also test their ability to support myofibers in vitro and whether activation of ? catenin impairs it. Our long-term goal is to interrupt the vicious circle of fibrosis damaging the tissue and this resulting in more fibrosis. The first step toward such goal, and the subject of this application, is to identify the mechanisms with which fibrosis damages the tissue in the first place.